Scientific Publications

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247 Results

2018

Paternally inherited cis-regulatory structural variants are associated with autism

Brandler WM, Antaki D, Gujral M, Kleiber ML, Whitney J, Maile MS, Hong O, Chapman TR, Tan S, Tandon P, Pang T, Tang SC, Vaux KK, Yang Y, Harrington E, Juul S, Turner DJ, Thiruvahindrapuram B, Kaur G, Wang Z, Kingsmore SF, Gleeson JG, Bisson D, Kakaradov B, Telenti A, Venter JC, Corominas R, Toma C, Cormand B, Rueda I, Guijarro S, Messer KS, Nievergelt CM, Arranz MJ, Courchesne E, Pierce K, Muotri AR, Iakoucheva LM, Hervas A, Scherer SW, Corsello C, Sebat J.

Science. 2018 Apr 20;360(6386):327-331. doi: 10.1126/science.aan2261. ABSTRACT The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent. PMID:29674594 | PMC:PMC6449150 | DOI:10.1126/science.aan2261

April 21, 2018

Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM)

Thomas J, Levy H, Amato S, Vockley J, Zori R, Dimmock D, Harding CO, Bilder DA, Weng HH, Olbertz J, Merilainen M, Jiang J, Larimore K, Gupta S, Gu Z, Northrup H; PRISM investigators.

Mol Genet Metab. 2018 May;124(1):27-38. doi: 10.1016/j.ymgme.2018.03.006. Epub 2018 Mar 31. ABSTRACT BACKGROUND: Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. METHODS: Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600 μmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5 mg/day to 60 mg/day. RESULTS: Of 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 μmol/L, 60.7% of participants achieved blood Phe ≤360 μmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 μmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6 months of exposure (early treatment phase) than after 6 months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. CONCLUSION: Results from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment. PMID:29653686 | DOI:10.1016/j.ymgme.2018.03.006

April 15, 2018

Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization

Farnaes L, Hildreth A, Sweeney NM, Clark MM, Chowdhury S, Nahas S, Cakici JA, Benson W, Kaplan RH, Kronick R, Bainbridge MN, Friedman J, Gold JJ, Ding Y, Veeraraghavan N, Dimmock D, Kingsmore SF. 

NPJ Genom Med. 2018 Apr 4;3:10. doi: 10.1038/s41525-018-0049-4. eCollection 2018. ABSTRACT Genetic disorders are a leading cause of morbidity and mortality in infants. Rapid whole-genome sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants. We report a retrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016-March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands also received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points. The diagnostic sensitivity of rWGS was 43% (eighteen of 42 infants) and 10% (four of 42 infants) for standard genetic tests (P = .0005). The rate of clinical utility of rWGS (31%, thirteen of 42 infants) was significantly greater than for standard genetic tests (2%, one of 42; P = .0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had a 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800,000-$2,000,000. These findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting. PMID:29644095 | PMC:PMC5884823 | DOI:10.1038/s41525-018-0049-4

April 13, 2018
Infant MortalityrWGS

Early life experience shapes neural genome

Song S, Gleeson JG.

Science. 2018 Mar 23;359(6382):1330-1331. doi: 10.1126/science.aat3977. NO ABSTRACT PMID:29567692 | DOI:10.1126/science.aat3977

March 24, 2018

The case for early use of rapid whole-genome sequencing in management of critically ill infants: late diagnosis of Coffin-Siris syndrome in an infant with left congenital diaphragmatic hernia, congenital heart disease, and recurrent infections

Sweeney NM, Nahas SA, Chowdhury S, Campo MD, Jones MC, Dimmock DP, Kingsmore SF; RCIGM Investigators. 

Cold Spring Harb Mol Case Stud. 2018 Jun 1;4(3):a002469. doi: 10.1101/mcs.a002469. Print 2018 Jun. ABSTRACT Congenital diaphragmatic hernia (CDH) results from incomplete formation of the diaphragm leading to herniation of abdominal organs into the thoracic cavity. CDH is associated with pulmonary hypoplasia, congenital heart disease, and pulmonary hypertension. Genetically, it is associated with aneuploidies, chromosomal copy-number variants, and single gene mutations. CDH is the most expensive noncardiac congenital defect. Management frequently requires implementation of extracorporeal membrane oxygenation (ECMO), which increases management expenditures 2.4-3.5-fold. The cost of management of CDH has been estimated to exceed $250 million per year. Despite in-hospital survival of 80%-90%, current management is imperfect, as a great proportion of surviving children have long-term functional deficits. We report the case of a premature infant prenatally diagnosed with CDH and congenital heart disease, who had a protracted and complicated course in the intensive care unit with multiple surgical interventions, including postcardiac surgery ECMO, gastrostomy tube placement with Nissen fundoplication, tracheostomy for respiratory failure, recurrent infections, and developmental delay. Rapid whole-genome sequencing (rWGS) identified a de novo, likely pathogenic, c.3096_ 3100delCAAAG (p.Lys1033Argfs*32) variant in ARID1B, providing a diagnosis of Coffin-Siris syndrome. Her parents elected palliative care and she died later that day. PMID:29549119 | PMC:PMC5983173 | DOI:10.1101/mcs.a002469

March 18, 2018

Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters

Sweeney TE, Azad TD, Donato M, Haynes WA, Perumal TM, Henao R, Bermejo-Martin JF, Almansa R, Tamayo E, Howrylak JA, Choi A, Parnell GP, Tang B, Nichols M, Woods CW, Ginsburg GS, Kingsmore SF, Omberg L, Mangravite LM, Wong HR, Tsalik EL, Langley RJ, Khatri P.

Crit Care Med. 2018 Jun;46(6):915-925. doi: 10.1097/CCM.0000000000003084. ABSTRACT OBJECTIVES: To find and validate generalizable sepsis subtypes using data-driven clustering. DESIGN: We used advanced informatics techniques to pool data from 14 bacterial sepsis transcriptomic datasets from eight different countries (n = 700). SETTING: Retrospective analysis. SUBJECTS: Persons admitted to the hospital with bacterial sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A unified clustering analysis across 14 discovery datasets revealed three subtypes, which, based on functional analysis, we termed “Inflammopathic, Adaptive, and Coagulopathic.” We then validated these subtypes in nine independent datasets from five different countries (n = 600). In both discovery and validation data, the Adaptive subtype is associated with a lower clinical severity and lower mortality rate, and the Coagulopathic subtype is associated with higher mortality and clinical coagulopathy. Further, these clusters are statistically associated with clusters derived by others in independent single sepsis cohorts. CONCLUSIONS: The three sepsis subtypes may represent a unifying framework for understanding the molecular heterogeneity of the sepsis syndrome. Further study could potentially enable a precision medicine approach of matching novel immunomodulatory therapies with septic patients most likely to benefit. PMID:29537985 | PMC:PMC5953807 | DOI:10.1097/CCM.0000000000003084

March 15, 2018

Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas

Li H, Byers HM, Diaz-Kuan A, Vos MB, Hall PL, Tortorelli S, Singh R, Wallenstein MB, Allain M, Dimmock DP, Farrell RM, McCandless S, Gambello MJ.

Mol Genet Metab. 2018 Apr;123(4):428-432. doi: 10.1016/j.ymgme.2018.02.016. Epub 2018 Feb 27. ABSTRACT Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI. PMID:29510902 | DOI:10.1016/j.ymgme.2018.02.016

March 8, 2018
RPM for NICU and PICU

The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants

Petrikin JE, Cakici JA, Clark MM, Willig LK, Sweeney NM, Farrow EG, Saunders CJ, Thiffault I, Miller NA, Zellmer L, Herd SM, Holmes AM, Batalov S, Veeraraghavan N, Smith LD, Dimmock DP, Leeder JS, Kingsmore SF.

NPJ Genom Med. 2018 Feb 9;3:6. doi: 10.1038/s41525-018-0045-8. eCollection 2018. ABSTRACT Genetic disorders are a leading cause of morbidity and mortality in infants in neonatal and pediatric intensive care units (NICU/PICU). While genomic sequencing is useful for genetic disease diagnosis, results are usually reported too late to guide inpatient management. We performed an investigator-initiated, partially blinded, pragmatic, randomized, controlled trial to test the hypothesis that rapid whole-genome sequencing (rWGS) increased the proportion of NICU/PICU infants receiving a genetic diagnosis within 28 days. The participants were families with infants aged <4 months in a regional NICU and PICU, with illnesses of unknown etiology. The intervention was trio rWGS. Enrollment from October 2014 to June 2016, and follow-up until November 2016. Of all, 26 female infants, 37 male infants, and 2 infants of undetermined sex were randomized to receive rWGS plus standard genetic tests (n = 32, cases) or standard genetic tests alone (n = 33, controls). The study was terminated early due to loss of equipoise: 73% (24) controls received genomic sequencing as standard tests, and 15% (five) controls underwent compassionate cross-over to receive rWGS. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days of enrollment (the primary end-point) to be higher in cases (31%, 10 of 32) than controls (3%, 1 of 33; difference, 28% [95% CI, 10-46%]; p = 0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, 7 of 22) than controls (0%, 0 of 23; difference, 32% [95% CI, 11-53%];p = 0.004). Median age at diagnosis (25 days [range 14-90] in cases vs. 130 days [range 37-451] in controls) and median time to diagnosis (13 days [range 1-84] in cases, vs. 107 days [range 21-429] in controls) were significantly less in cases than controls (p = 0.04). In conclusion, rWGS increased the proportion of NICU/PICU infants who received timely diagnoses of genetic diseases. PMID:29449963 | PMC:PMC5807510 | DOI:10.1038/s41525-018-0045-8

February 17, 2018
Infant MortalityrWGS

A community approach to mortality prediction in sepsis via gene expression analysis

Sweeney TE, Perumal TM, Henao R, Nichols M, Howrylak JA, Choi AM, Bermejo-Martin JF, Almansa R, Tamayo E, Davenport EE, Burnham KL, Hinds CJ, Knight JC, Woods CW, Kingsmore SF, Ginsburg GS, Wong HR, Parnell GP, Tang B, Moldawer LL, Moore FE, Omberg L, Khatri P, Tsalik EL, Mangravite LM, Langley RJ.

Nat Commun. 2018 Feb 15;9(1):694. doi: 10.1038/s41467-018-03078-2. ABSTRACT Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance is validated in five cohorts of community-onset sepsis patients in which the models show summary AUROCs ranging from 0.765-0.89. Similar performance is observed in four cohorts of hospital-acquired sepsis. Combining the new gene-expression-based prognostic models with prior clinical severity scores leads to significant improvement in prediction of 30-day mortality as measured via AUROC and net reclassification improvement index These models provide an opportunity to develop molecular bedside tests that may improve risk stratification and mortality prediction in patients with sepsis. PMID:29449546 | PMC:PMC5814463 | DOI:10.1038/s41467-018-03078-2

February 17, 2018

Defining the phenotypic spectrum of SLC6A1 mutations

Epilepsia. 2018 Feb;59(2):389-402. doi: 10.1111/epi.13986. Epub 2018 Jan 8.

ABSTRACT

OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients.

METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects.

RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg).

SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.

PMID:29315614 | PMC:PMC5912688 | DOI:10.1111/epi.13986

January 10, 2018

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